@article{a7eb687194914bc1b94481dda77b6201,
title = "Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside",
abstract = "We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.",
keywords = "autoantibody, autoantigen, clinical research/practice, heart transplantation/cardiology, histocompatibility, immunogenetics, microarray/protein array, organ transplantation in general, rejection, translational research/science",
author = "Butler, {Carrie L.} and Hickey, {Michelle J.} and Ning Jiang and Ying Zheng and David Gjertson and Qiuheng Zhang and Ping Rao and Fishbein, {Gregory A.} and Martin Cadeiras and Deng, {Mario C.} and Banchs, {Hector L.} and Guillermo Torre and David DeNofrio and Eisen, {Howard J.} and Jon Kobashigawa and Starling, {Randall C.} and Abdallah Kfoury and {Van Bakel}, Adrian and Gregory Ewald and Ivan Balazs and Baas, {Arnold S.} and Daniel Cruz and Reza Ardehali and Reshma Biniwale and Murray Kwon and Abbas Ardehali and Ali Nsair and Bryan Ray and Reed, {Elaine F.}",
note = "Funding Information: This work was supported in part by a grant from Immucor, Inc, NIAID R01 AI024819, R01 AI135201 (to Dr Reed), and an NIDDK T32 fellowship (to Dr Butler). The multicenter cohort was a sub‐study of the phase 3 clinical trial sponsored by Novartis ( www.ClinicalTrials.gov NCT00300274). The authors thank all individuals and centers involved in the collection and maintenance of the multicenter cohort patient sera including: Cleveland Clinic, Drexel, LDS Hospital, Cardiology Methodist, Medical University of South Carolina, Tufts, UCLA, University of Puerto Rico, and Washington University. We also extend our gratitude to the staff of the UCLA Immunogenetics Center for maintenance of the biorepository sera and HLA typing of endothelial cells. Finally, the authors hereby express their thanks for the cooperation of OneLegacy and gratitude to the organ and tissue donors and their families, for giving the gift of life and the gift of knowledge, facilitated by their generous donation. Funding Information: The authors of this manuscript have conflicts of interest to disclose as described by the . Drs Jiang, Balazs, and Bryan Ray are employees of Immucor, Inc. Dr Reed has an investigator‐initiated research grant from Immucor, Inc. American Journal of Transplantation Funding Information: This work was supported in part by a grant from Immucor, Inc, NIAID R01 AI024819, R01 AI135201 (to Dr Reed), and an NIDDK T32 fellowship (to Dr Butler). The multicenter cohort was a sub-study of the phase 3 clinical trial sponsored by Novartis (www.ClinicalTrials.gov NCT00300274). The authors thank all individuals and centers involved in the collection and maintenance of the multicenter cohort patient sera including: Cleveland Clinic, Drexel, LDS Hospital, Cardiology Methodist, Medical University of South Carolina, Tufts, UCLA, University of Puerto Rico, and Washington University. We also extend our gratitude to the staff of the UCLA Immunogenetics Center for maintenance of the biorepository sera and HLA typing of endothelial cells. Finally, the authors hereby express their thanks for the cooperation of OneLegacy and gratitude to the organ and tissue donors and their families, for giving the gift of life and the gift of knowledge, facilitated by their generous donation. Publisher Copyright: {\textcopyright} 2020 The American Society of Transplantation and the American Society of Transplant Surgeons",
year = "2020",
month = oct,
day = "1",
doi = "10.1111/ajt.15863",
language = "English (US)",
volume = "20",
pages = "2768--2780",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Elsevier B.V.",
number = "10",
}